Embryonic vertebrate central nervous systemRevised terminology.

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SPECIAL COMMUNICATION
Embryonic Vertebrate Central Nervous System:
Revised Terminology
THE BOULIIER COMMITTEE 1
JAY B. ANGEVINE, JR.
Department of Anatomy
College of Medicine
University of Arizona
Tucson, Arizona 85721
DAVID BODIAN
Department of Anatomy
The Johns Hopkins University
School of Medicine
Baltimore, Maryland 21205
ALFRED J. COULOMBRE
National Eye Institute
National Institutes of Health
Bethesda, Maryland 20014
VIKTOR HAMBURGER
Department of Biology
Washington Ur;:iversity
St. Louis, Missouri 63130
MARCUS JACOBSON
jenkins Biophy.iics Department
The Johns Hoprzins University
Baltimore, Maryland 21218
KATHERINE iVI. LYSER
Department of .Biological Sciences
Hunter College of the
City University of New York
New York, Neu' York 10021
MAC V. EDDS, JR.
Department of Biology
Brown Universitu
Providence, Rhoze Island 02912
MARTIN C. PRESTIGE
Department of Physiology
Edinburgh University
Medical School
Teriot Place
Edinburgh, Scotland EH 8-9AG
RICHARD L. SIDMAN
Department of Neuropathology
Haruard Medical School
Boston, Massachusetts 02115
SILVIO VARON
Department of Biology
University of California at
a t Sun Diego
La Jolla, California 92037
PAUL A. WEISS
The Rockefeller University
New York, New York 10021
ABSTRACT
The layers and cells of the early developing central nervous system
lack direct counterparts i n the adult and must be designated by a special terminology.
The inconsistent and inaccurate langua,ze now in use leads to misunderstanding and
a revision is proposed in which the four fundamental zones are termed the ventricular,
subventricular, intemediate, and marginal zones. Each is defined according to the
form, behavior, and fate of its constituent cells. All neurons and macroglia of the
central nervous system can be derived from these developmental zones.
Our concepts of cell behavior in developing vertebrate nervous systems have
changed in recent years with the application of cytophotometric, autoradiographic,
and electron microscopic methods (Watterson, '65; Fujita, '66; Sidman, '70). The
basic terminology was formulated more
than 80 years ago by His (1889, '04) to
describe the idea that germinal cells divide
at the ventricular surface of the central
nervous system (CNS) and generate postmitotic neuroblasts which move outward
from that surface, through interstices in :i
broad syncytial mass of spmgioblasts, to
constitute a mantle layer; a cell-poor marginal layer forms the outermost component
of the CNS. Increasing recognition of the
inadequacies of this formulation and terminology has led contemporary workers to
use a variety of alternative names. The
ANAT. REC., 166: 257-262.
participants in a recent conference on Development of the Nervous System at Boulder, Colorado recognized that the descriptive language has become so varied as to
impair communication and blur recognition of what are the unsolved problems.
The following recommendations are offered by a self-appointed "Boulder Committee" with the awareness that such
terminological problems are among the
inevitable (and perhaps desirable) conseReceived Dec. 2, '69. Accepted Dec. 5, '69.
1 This report grew out of discussions at a conference
entitled Intensive Study Program in the Neurosciences
held at Boulder, Colorado from July 21 to August 8,
1969, under the auspices of the Neurosciences Research Program. The conference will be published as
a book, Th? Neurosciences: Second Study Program.
F. 0. Schmitt, editor-in-chief. The Rockefeller University Press, New York, N. Y. In press. Please send reprint requests to Dr. Richard L. Sidman, Department
of Neuropathology, Harvard Medical School, 25 Shatturk Street. Boston, Massachusetts 02115.
2 See footnote 1.
257
258
THE BOULDER COMMITTEE
quences of scientific advance and with the
hope that the pace of further progress will
render these recommendations obsolete in
less than the span of years served by His's
terms.
The embryonic CNS consists of four fundamental zones from which the adult organization is derived, though none of the
four corresponds directly to any adult component. We propose the geographical
names ventricular zone, subventricular
zone, intermediate zone, and marginal zone
(fig. 1).
The ventricular zone contains only ventricular cells, this term replacing His's germinal and spongioblast cells. Modern cytological methods have proved that these
cells are simply the mitotic and intermitotic forms of a single pseudostratified columnar epithelial cell (Sauer, '35a,b; Sidman et al., '59; Fujita, '63; Stensaas and
Stensaas, '68). The columnar cell replicates its DNA, the nucleus moves toward
the ventricular surface as the cell rounds
up, mitosis takes place at the ventricular
surface, and the daughter nuclei then move
outward as the cells elongate to the original columnar form (fig. 1, A-C). The ventricular zone is defined as the space to
which this to-and-fro nuclear movement
A
B
is confined. The ventricular cells are the
ultimate progenitors of all neurons and
macroglial cells of the CNS and the zone
will become attenuated and eventually will
disappear as its cells become transformed
(fig. 1, D-E).
The marginal zone is recognizable shortly after formation of the ventricular zone
as a cell-sparse layer composed of the outermost cytoplasmic parts of the ventricular
cells (fig. 1, B). This zone contains no primary cell type of its own and the nuclei of
the ventricular cells do not enter it. The
width of the marginal zone in a sense increases progressively during embryonic development as the ventricular cells elongate,
but the inner parts of the marginal zone
come to be occupied by intermediate and
subventricular components as described below, so that a better policy is to designate
as marginal zone only an outermost layer
of fairly constant form (fig. 1, C-E). Histological preparations stained by Golgi's
method show that in older embryos the
cytoplasmic processes in the marginal layer
are attenuated, branched, and intertwined;
it remains to be learned whether the elongated cells bearing such processes continue
to round up at the ventricular surface
and divide. Eventually the marginal zone
C
D
E
Fig. 1 Schematic drawing of five stages (A-E) in the development of the vertebrate central nervous system, as described in the text. Abbreviations: CP, cortical plate; I, intermediate zone; M,
marginal zone; S, subventricular zone; V, ventricular zone.
EMBRYONIC NERVOUS SYSTEM TERMINOLOGY
is replaced by ingrowing axons, dendrites,
and synaptic terminals, the relative numbers varying among CNS regions and
among species.
The intermediate zone is the third 1.0
form. Some progeny of dividing ventricnlar cells migrate outward and establish
this new zone at the junction between the
ventricular and marginal zones (fig. 1, C ).
The early cellular occupants of the intermediate zone are immature neurons that
are destined never to divide again, at least
under the usual conditions of life. These
cells emit axons which either course
through the intermediate zone and come to
interrelate different cell groups that will
differentiate within it or pass outward to
enter the marginal zone. The intermediate
zone remains relatively simple in some rchgions such as the anterior horn of the spinal cord but becomes very complex in some
other regions as secondary rearrangements
of cells occur within it (Levi-Montalcinii,
'63, '64; Kdlkn, '65). In cerebrum and
cerebellum, cell bodies migrate or become
displaced through it from within outwards
to form a cortical plate at the junction of
intermediate and marginal zones (CP in
fig. 1, D-E). At the same time, afferent
axons generated by distant cell bodies invade the expanding intermediate zone (fig.
1, D ) and the newly forming cortical neupons emit efferent axons that pass inward
across some part of it (fig. 1, E). Finally,
neuronal and macroglial cells enter it from
the subventricular zone, to be described
next.
The subventricular zone, located at the
junction of the ventricular and intermediate zones, has received less attention than
the other three cardinal zones. The initial
cellular occupants come into position so011
after the intermediate zone has begun to
form (fig. 1, D). Subventricular cells an:
small and round or oval. They are distinguished from the young neurons of the
intermediate zone by their proliferative activity and, unlike ventricular cells, they
remain stable in position, without a to-andfro nuclear displacement, during the mitotic cycle. The zone is probably preseni.
in every region of the embryonic CNS ai:
some time or other but i t is particularly
prominent in the cerebral hemispheres,
259
where i t continues to adulthood in many
species and has been called the subependymal layer (Allen, '12; Globus and Kuhlenbeck, '44; Smart, '61; Hinds, '68; Blakemore, '69). The subventricular zone gives
rise to special classes of neurons and to all
macroglia of the CNS with the possible exception of ependymal cells. In the spinal
cord it may generate predominantly or exclusively macroglia but in particular regions the zone expands to form special
neuron-generating embryonic structures
such as the rhombic lip at the lateral margins of the fourth ventricle and the ganglionic eminence in the floor of the lateral
ventricles (Essick, '07, '09, '12; Taber
Pierce, '66; Rakic and Sidman, '69).
In anticipation of objections to a modified terminology, we must comment further on certain of the older terms. Our
ventricular zone has been known under
several other guises (Russell and Rubinstein, '63; Fujita, '64; Langman, '68). The
term matrix (matrix laye?.) is unsatisfactory because it refers also to intercellular
materials and, more importantly, it does
not distinguish between the ventricular
and subventricular zones. Medulloepithelial layer, favored by some pathologists,
likewise does not discriminate clearly
among the immature components of the
CNS; thus medulloepithelioma is used to
designate a very undifferentiated CNS tumor, while medulloblastoma denotes a cerebellar tumor that likely is referable to
a subventricular component. Primitive
ependyma is inaccurate, for the zone is an
anlage of much more than the ependyma;
indeed, the ependyma possibly may arise directly from the subventricular zone instead.
Maternal layer, an old French designation, is appropriate but perhaps too vague.
Neuroepithelial layer, as a name specifically for this zone, implies that the rest of
the developing and adult CNS is something other than a neuroepithelium; further, this term should retain a more general connotation so that, for example, one
can characterize a CNS cell as neuroepithelial (as opposed to, say, mesenchymal)
in origin without speci€ying from which
of the four proposed fundamental zones it
was derived. Our intermediate zone incorporates both the mantle and intermediate
260
THE BOULDER COMMITTEE
zones of His (see above). Our subventricu- Essick, C. R. 1907 The corpus ponto-bulbare a hitherto undescribed nuclear mass in the hular zone is probably comparable in part to
man hind brain. Am. J. Anat., 7: 119-136.
the adult subependymal layer (see above)
1909 On the embryology of the corpus
ponto-bulbare and its relation to the developbut the latter name would cause confusion
the pons. Anat. Rec., 3: 254-257.
if applied a t embryonic stages when no -- ment of1912
The development of the nuclei
ependyma yet exists (fig. 1, D-E).
pontis and the nucleus arcuatus in man. Am.
J. Anat., 13: 25-54.
A few comments on the constituent cells
are in order. No basis exists today for as- Fujita, S. 1963 The matrix cell and cytogenesis in the developing central nervous system. J.
signing more specific names to cells of the
Comp. Neur., 120: 3 7 4 2 .
innermost two zones than is indicated by
1964 Analysis of neuron differentiation
in the central nervous system by tritiated thythe terms ventricular cell and subventricumidine autoradiography. J. Comp. Neur., 122:
Zar cell. All ventricular cells are identical
31 1-328.
in structure and behavior by every avail1966 Applications of light and electron
microscopic autoradiography to the study of
able criterion, though it is quite possible
cytogenesis of the forebrain. In: Evolution of
that different clones will be shown to exist
the Forebrain, Phylogenesis and Ontogenesis
among them. Subventricular cells fall int9
of the Forebrain. R. Hassler and H. Stephan,
eds. G. Thieme, Stuttgart, pp. 180-196.
two classes based on cell size and nuclear
morphology; cells of both classes prolifer- Globus, J. H., and H. Kuhlenbeck 1944 The
subependymal cell plate (matrix) and its reate and the possible interrelationships relationship to brain tumors of the ependymal
type. J. Neuropath. Exp. Neurol., 3: 1-35.
main to be worked out (Schaper, 1894,
1897a,b; Kershman, '38; Kuhlenbeck, '50; Hinds, J . W. 1968 Autoradiographic study of
histogenesis in the mouse olfactory bulb. 11.
Sidman, '68; Rakic and Sidman, '68). Some
Cell proliferation and migration. J. Camp.
o i the cells derived from this zone slowly
Neur., 134: 305-322.
migrate into the intermediate and margin- His, W. 1889 Die Neuroblasten und deren Entstehung im embryonalen Mark. Arch. Anat.
al zones and proliferate as they go. ThosE
Physiol., Anat. Abt., 1889: 249-300.
of the proliferating cells which come to
1904 Die Entwicklung des menschlichen Gehirn w a r e n d der ersten Monate. S. HirFossess morphological proFerties of macrozel, Leipzig, 176 pp.
giial cells may be termed glioblasts. I n KalICn,
B. 1965 Early morphogenesis and patturn, some daughter cells take on certain
tern formation in the central nervous svstem.
In: Organogenesis. R. L. DeHaan and H. Urastrocytic features while continuing to
sprung, eds. Holt, Rinehart and Winstcn, New
multiply and may be named astrohlasts
York, pp. 107-128.
(Vaughn, '69).
Kershman, J. 1938 The medulloblast and the
One special problem of nomenclature
medulloblaetoma. A study of human embryos.
A. M. A. Arch. Neur. Psychiat., 40:937-957.
must be acknowledged, though it js not yet
H. 1950 The transitory superficial
ripe for solution. The term neuroblast lacks Kuhlenbeck,
granular layer of the cerebellar cortex. Its reprecision. The suffix -blast commonly,
lationship to certain cerebellar neoplasms. Am.
though not always, connotes a proliferatMed. Women's Assn. Journal, 5: 347-351.
ing cell, whereas the vertebrate neuroblast Langman, J. 1968 Histogenesis of the central
nervous system, In: The Structure and Funcis postmitotic. A useful terminology for
tion of Nervous Tissue. G. H. Bourne, ed. Acaimmature nerve cells cannot be assigned
demic Press, New York, pp. 33-65.
until investigators ( 1 ) identify a prolifer- Levi-Montalcini, R. 1963 Growth and differentiation in the nervous system. In: The Nature
ating cell whose progeny will differentiate
of Biological Diversity. J. Allen, ed. McGrawexclusively into neurons and ( 2 ) establish
Hill, New York, pp. 261-295.
whether and when a cell becomes commit1964 Events i n the developing nervous
system. In: Progress i n Brain Research. Growth
ted to a particular form, set of synaptic
and Maturation of the Brain. D. P. Purpura
connections, and functional properties.
LITERATURE CITED
Allen, E. 1912 The cessation of mitosis in the
central nervous system of the albino rat. J.
Comp. Neur., 22: 547-568.
Blakemore, W. F. 1969 The ultrastructure of
the subependymal plate in the rat. J. Anat.,
104: 423-433.
and J. P. Schade, eds. Elsevier, Amsterdam, 4:
1-29.
Rakic, P., and R. L. Sidman 1968 Subcommissural organ and adjacent ependyma: Autoradiographic study of their origin i n the mouse
brain. Am. J. Anat., 122: 317-336.
1969 Telencephalic origin of pulvinar
neurons in the fetal human brain. 2. Anat. Entwicklungsgesch., 129: 53-82.
-
EMBRYONIC NERVOUS SYSTEM TERMINOLOGY
Russell, D. S . , and L. J . Rubinstein 1963 Pathology of Tumours of the Nervous System, \Villiams and Wilkins, Baltimore, 2nd edition.
Sauer, F. C. 1935a Mitosis in the neural tL.be.
J. Comp. Neur., 62: 377-405.
1935b The cellular structure of the
neural tube. J. Comp. Neur., 63: 13-23.
Schaper, A. 1894 Die morphologische und liistologische Entwicklung des Kleinhirns der T8:leostier. Anat. Anz., 9: 489-501.
1897a Die friihesten Differenzierurgsvorgange im Centralnervensystem. Arch. E,ntwicklungsmech., 5: 81-132.
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the central nervous system of vertebrates. Science, 5: 430-431.
Schmitt, F. O., editor-in-chief. The Neurosciences:
Second Study Program. The Rockefeller University Press, New York, N. Y. I n press.
Cidman, R. L. 1958 Cell proliferation and inigration i n the developing brain. In: Drugs and
Poisons i n Relation to the Developing Nervous
System. G. M. McKhann and S. J. Yaffe, eds.
U. S. Public Health Service Publ. No. 1791,
Washington, D. C., pp. 5-11.
-__- 1970 Autoradiographic methods and
principles for the study of the nervous system
with thymidine-W. In: Contemrora-v Research
Techniques of Neuroanatomy. S. 0. E. Ebbesson
261
and W. J . H. Nauta, eds. Springer-Verlag, New
York, in press.
Sidman, R. L., I. L. Miale and N. Feder 1959
Cell proliferation and migration in the primitive ependymal zone; an autoradiographic study
of histogenesis in the nervous system. Exp.
Neurol., 1 : 322-333.
Smart, I. 1961 The subependymal layer of the
mouse brain and its cell production as shown
by radioautography after thymidine-H3 injection. J. Comp. Neur., 116: 325-317.
Stensaas, L. J., and S. S. Stensaas 1968 An
electron microscope study of cells i n the matrix
and intermediate laminae of the cerebral hemisphere of the 4 5 mm rabbit embryo. Z. Zellforsch., 91: 341-365.
Taber Pierce, E. 1966 Histogenesis of the nuclei griseum pontis, corporis pontobulbarls and
reticularis tegmenti pontis (Bechterew) in the
mouse. A n autoradiographic study. J. Comp.
Neur., 126: 219-240.
Vaughn, J. E. 1969 An electron microscopic
analysis of gliogenesis in rat optic nerves. Z.
Zellforsch., 94: 293-324.
Watterson, R. L. 1965 Structure znd mitotic
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Hoit, Rinehzrt and Winston, Nzw Y x k . ~ p .
129-159.
As ideas are preserved and 4communicated by means of words it
necessarily follows that we cannot improve the language of any
science without at the samti time improving the science itself,
neither can we, on the other hand, improve a science without improving the language or nom.enclature which belongs to it. However certain the facts of any science may be, and however just the
ideas we have formed of these facts, we can only communicate false
impressions to others while we waizt words by which these may be
properly expressed.
Lavoisier, “Elements of Chemistry,” Preface